This invention relates to a method of preparation of granules incorporating a medicament for pharmaceutical use.
Granules are a suitable form for medicaments which are to be administered orally. A dose of medicament in the form of granules may be measured and administered by incorporating into a sachet or using a spoon or may be incorporated into a capsule of formulated into a tablet to be swallowed. It is preferred that such granules are of regular shape and substantially spherical to give good fluidity for ease of dispensing and capsule filling or tabletting as well as for aesthetic appeal. Spherical granules are also easier to coat with taste masking, enteric/protective and sustained release coating materials.
At present, there are two methods of preparing spherical granules. One is to extrude a cylindrical granule using a xe2x80x9csqueeze-outxe2x80x9d type granulation machine and then to make it spherical in shape by using a marumeriser, a machine which xe2x80x9ccuts off the edgesxe2x80x9d of the cylinder shape. This method involves difficult manufacturing conditions and is time consuming which precludes its routine use. The other method used is to gradually coat a core particle such as granulated sugar using a centrifugal flow type granulator but this is a time consuming process and is not generally applicable to a wide range of medicaments where the proportion of the volume of the medicament in the granules high (20% or higher).
The most efficient method of preparing granules is using a high-speed agitation granulator machine which mixes and granulates in one operation using two rotating blades, a main blade with a horizontal plane of rotation and a chopper blade above it with a vertical plane of rotation (cross blade). The medicament and excipients are introduced into the machine in advance and binder solution is then poured or sprayed into the machine from above whilst the blades are rotating. By this method, granules can be prepared quickly and easily but the disadvantage is that the resulting granules are irregular and non-spherical in shape and do not have the advantages associated with spherical granules.
Surprisingly, we have now discovered a method of preparing substantially spherical granules using a high-speed agitation granulator machine thus avoiding the need to use the xe2x80x9csqueeze-outxe2x80x9d and marumerizer method.
Accordingly, the present invention provides a high speed agitation granulator method of preparing a substantially spherical granule for pharmaceutical use comprising a medicament for pharmaceutical use wherein the medicament has an aqueous solubility of 0.01 to 0.30 g/ml, which method comprises introducing a mixture of the medicament and excipients comprising at least 5% crystalline cellulose into the granulator and spraying on water or a mixture of ethanol and water as binder solution.
Suitable medicaments include caffeine which has an aqueous solubility 0.02 g/ml, pyridoxine hydrochloride which has an aqueous solubility of 0.22 g/ml and particularly the orally administered antiviral compounds, famciclovir and acyclovir which have a aqueous solubility of more than 0.25 g/ml. Generally the proportion of medicament with respect to excipients in the composition of the granule is up to 25%, such as up to 5%, 10%, 20%, although it is envisaged that up to 55% medicament could be incorporated.
The mixture of medicament and excipients comprise at least 5% crystalline cellulose, for example up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% and 90%. Other suitable additional excipients include lactose, although the highest yield of spherical granules are when the mixture contains crystalline cellulose as the sole excipient, for example where the composition contains 25% medicament and 75% crystalline cellulose.
The binder solution may be up to 75% ethanol and it is found that the sphericity of granules is higher when the ethanol concentration is higher although from a manufacturing environment point of view and to avoid any problems resulting from residual organic solvent, it may be preferable to use pure water as the binder solution. A linear relationship between the granule size and the amount of binder solution was observed such that the granule size can be regulated by this method (the greater the amount of binder solution, the larger the granule). The granules suitable for administration by spoon are generally more than 500 um in diameter, favourably more than 700 um, up to 1500 um, favourably up to 1000 um. Granules suitable for capsules or tablets are usually smaller than 500 um.
The granules are suitably agitated in the granulator after spraying of the binder solution to improve the spherical shape and smooth the surface of the granules. The agitation time will depend on the size of the granules and composition of the granules, together with the size of the granulator and the speed of rotation of the main blade and the cross blade. The agitation times generally range from 2 to 30 minutes.
The invention provides, in one aspect, a substantially spherical granule for pharmaceutical use comprising famciclovir and 5% or more crystalline cellulose, together with an optional coating. In a preferred aspect the invention provides such a granule comprising famciclovir and crystalline cellulose as the sole excipient, for example a granule containing 25% famciclovir and 75% cellulose.
The following Examples illustrate the process of the invention. The accompanying Figures and Tables illustrate the following with respect to pyridoxine granules: